Pesticide residues in food — 2006: Toxicological ... - ipcs inchem

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Groups of 17 male and 17 female Sprague-Dawley rats received a single oral (gavage) dose
of pirimiphos-methyl at 0, 15, 150 or 1500 mg/kg bw in corn oil. In each group, seven animals
of each sex were used for neuropathology analysis and ten animals of each sex were allocated for
cholinesterase evaluation. Animals were checked daily for viability and clinical signs. Body weight
was measured before the test and on days 0, 1, 7, 14 and 15 of treatment. A functional observation
battery (FOB) test and a locomotor activity test were performed before the test, at the time of peak
effect (± 24 h after dosing—study day 1) and on days 7 and 14 for the seven animals of each sex
per group used for neuropathology evaluation and for five animals of each sex per group used for
cholinesterase evaluation. In the animals used for cholinesterase evaluation, plasma and erythrocyte
cholinesterase activity was determined in five animals of each sex before initiation of dosing, at the
time of peak effect (± 24 h after dosing), and on days 7 and 15. Brain cholinesterase activity was
assessed in five animals of each sex per group at the time of peak effect (day 1) and at day 15. Blood
was collected at euthanization and whole brain weights and regional brain weights were recorded for
each animal. In the neuropathology group, all animals were euthanized on day 15 and perfused in
situ. A neurohistopathological examination was performed for five animals of each sex in the control
group and in the group at 1500 mg/kg bw. Statements of adherence to quality assurance and GLP
were included.
No mortality was observed. In animals at 1500 mg/kg bw, clinical signs typical of cholinesterase
inhibition were observed, i.e. tremors, lacrimation, staining on body surface, gait alterations, hunched
behaviour, exophthalmus, soft stools. These signs were predominantly observed on day 1, although in
some animals clinical signs were also observed on days 2–4. In the group at the highest dose, FOB
testing on day 1 revealed altered posture (sitting with head lowered, flattened), clonic convulsions
(whole body tremors), altered palpebral closure (eyelids drooping or half-closed), lacrimation,
salivation, soiled fur, red deposits around eyes, nose and mouth and chromodacryorrhea, catalepsy,
altered pupil response and righting reflex, decrease in body temperature, altered hindlimb extensor
strength and reduced forelimb and hindlimb grip strength and a reduced rotarod performance. Also,
in the group at the highest dose, the motor activity test on day 1 revealed decreased motor activity,
gait alterations (walking on tiptoes, hunched body, ataxia), clonic convulsions (whole body tremors;
slight or moderate), and decreased arousal and rearing activity. Loss of body weight in the group
at the highest dose was observed on the first day of testing. During the next 2 weeks, body weights
recovered to control levels. No clinical signs and no effects on FOB or locomotor activity parameters
were observed in animals at 15 and 150 mg/kg bw. Treatment with pirimiphos-methyl had no effect
on total brain weight, regional brain weight or brain histology in any of the treatment groups.
The effects of treatment with pirimiphos-methyl on cholinesterase activity on day 1 and day 15
are presented in Table 4.
Table 4. Cholinesterase activity (% of control values) in rats given a single oral dose of
pirimiphos-methyl by gavage
Effect
Dose (mg/kg bw)
15 150 1500
Male Female Male Female Male Female
Day 1
Plasma 79* 52* 45* 19* 8* 4*
Erythrocyte 74* 95 61* 79* 29* 37*
Brain sections:
Hippocampus 97 97 91 86* 35* 42*
Olfactory 91 93 88 94 36* 42*
PIRIMIPHOS-METHYL X-X JMPR 2006